Journal
NEOPLASIA
Volume 15, Issue 4, Pages 421-+Publisher
NEOPLASIA PRESS
DOI: 10.1593/neo.122098
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Funding
- National Institutes of Health [1R01DK62277, 1R01CA124414]
- Endowed Research Chair
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beta-Catenin is important in liver homeostasis as a part of Wnt signaling and adherens junctions (AJs), while its aberrant activation is observed in hepatocellular carcinoma (HCC). We have reported hepatocyte-specific beta-catenin knockout (KO) mice to lack adhesive defects as gamma-catenin compensated at AJ. Because gamma-catenin is a desmosomal protein, we asked if its increase in KO might deregulate desmosomes. No changes in desmosomal proteins or ultrastructure other than increased plakophilin-3 were observed. To further elucidate the role and regulation of gamma-catenin, we contemplate an in vitro model and show gamma-catenin increase in HCC cells upon beta-catenin knockdown (KD). Here, gamma-catenin is unable to rescue beta-catenin/T cell factor (TCF) reporter activity; however, it sufficiently compensates at AJs as assessed by scratch wound assay, centrifugal assay for cell adhesion (CAFCA), and hanging drop assays. gamma-Catenin increase is observed only after beta-catenin protein decrease and not after blockade of its transactivation. gamma-Catenin increase is associated with enhanced serine/threonine phosphorylation and abrogated by protein kinase A (PKA) inhibition. In fact, several PKA-binding sites were detected in gamma-catenin by in silico analysis. Intriguingly gamma-catenin KD led to increased beta-catenin levels and transactivation. Thus, gamma-catenin compensates for beta-catenin loss at AJ without affecting desmosomes but is unable to fulfill functions in Wnt signaling. gamma-Catenin stabilization after gamma-catenin loss is brought about by PKA. Catenin-sensing mechanism may depend on absolute beta-catenin levels and not its activity. Anti-beta-catenin therapies for HCC affecting total beta-catenin may target aberrant Wnt signaling without negatively impacting intercellular adhesion, provided mechanisms leading to gamma-catenin stabilization are spared.
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